Carvedilol adverse reactions

Carvedilol
COREG®, COREG CR® FDA Package Insert
Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied/Storage and Handling
Patient Counseling Information
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]

Adverse Reactions

Clinical Studies Experience

COREG has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction and in hypertensive subjects The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these patient populations are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks).

Heart Failure

• COREG has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received COREG for at least 6 months and 30% received COREG for at least 12months.
• In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with COREG for up to 5.9 years (mean: 4.8 years).
• Both in US clinical trials in mild-to-moderate heart failure that compared COREG in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared COREG in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).

Table 1 shows adverse events reported in subjects with mild‑to‑moderate heart failure enrolled in US placebo‑controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial:

• Shown are adverse events that occurred more frequently in drug‑treated subjects than placebo‑treated subjects with an incidence of >3% in subjects treated with carvedilol regardless of causality.
• Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild‑to‑moderate heart failure, and 10.4 months in the trial of severe heart failure subjects.
• The adverse event profile of COREG observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials.

Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with COREG in either the US placebo‑controlled trials in subjects with mild‑to‑moderate heart failure, or in subjects with severe heart failure in the COPERNICUS trial.

Incidence >1% to ≤3%

• Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.

• Cardiovascular: Fluid overload, ostural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.

• Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.

• Gastrointestinal: Melena, periodontitis.

• Liver and Biliary System: SGPT increased, SGOT increased.

• Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased.

• Musculoskeletal: Muscle cramps.

• Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocytopenia.

• Psychiatric: Somnolence.

• Reproductive male: Impotence.

• Special Senses: Blurred vision.

• Urinary System: Renal insufficiency, albuminuria, hematuria.

• Left Ventricular Dysfunction Following Myocardial Infarction

COREG has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received COREG and 980 who received placebo. Approximately 75% of the subjects received COREG for at least 6 months and 53% received COREG for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with COREG and placebo, respectively.

The most common adverse events reported with COREG in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in >3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with COREG:flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).

Hypertension

COREG has been evaluated for safety in hypertension in more than 2,193 subjects in US clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received COREG for at least 6 months. Most adverse events reported during therapy with COREG were of mild to moderate severity. In US controlled clinical trials directly comparing COREG in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of subjects receiving COREG discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo‑controlled trials increased with increasing dose of COREG. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg.

Table 2 shows adverse events in US placebo‑controlled clinical trials for hypertension that occurred with an incidence of ≥1% regardless of causality, and that were more frequent in drug‑treated subjects than placebo‑treated subjects.

Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo.

The following adverse events not described above were reported as possibly or probably related to COREG in worldwide open or controlled trials with COREG in subjects with hypertension or heart failure.

Incidence >0.1% to ≤1%

• Cardiovascular: Peripheral ischemia, tachycardia.

• Central and Peripheral Nervous System: Hypokinesia.

• Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions ].

• Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.

• Respiratory System: Asthma [see Contraindications ].

• Reproductive male: Decreased libido.

• Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.

• Special Senses: Tinnitus.

• Urinary System: Micturition frequency increased.

• Autonomic Nervous System: Dry mouth, sweating increased.

• Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.

• Hematologic: Anemia, leukopenia.

The following events were reported in ≤0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.

Laboratory Abnormalities

• Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with COREG. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with COREG and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with COREG.
• In a long-term, placebo-controlled trial in severe heart failure, subjects treated with COREG had lower values for hepatic transaminases than subjects treated with placebo, possibly because improvements in cardiac function induced by COREG led to less hepatic congestion and/or improved hepatic blood flow.
• COREG has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
• No clinically relevant changes were noted in fasting serum glucose in hypertensive patients; fasting serum glucose was not evaluated in the heart failure clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of COREG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Blood and Lymphatic System Disorders: Aplastic anemia.

• Immune System Disorders: Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).

• Renal and Urinary Disorders: Urinary incontinence.

• Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonitis.

• Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

References

Adapted from the FDA Package Insert.